Small Steps Add Up to Progress in NSCLC, a Clinical Context Report

CHARLES BANKHEAD: I'm Charles Bankhead of MedPage Today, and this is Expert Commentary, Non-Small Cell Lung Cancer. My guest is Dr. Lecia Sequist of the Massachusetts General Hospital. She is a thoracic medical oncologist at the MGH Cancer Center and is also assistant professor of medicine at Harvard.

Thank you for joining us.

LECIA SEQUIST, M.D.: Thanks for having me.

BANKHEAD: Could your start by giving us a little bit on the scope of the problem of non-small cell lung cancer? Have there been any notable changes in incidence, mortality, other aspects of epidemiology?

SEQUIST: Lung cancer is a big problem. It remains the No. 1 cancer killer in the United States and actually around the world. I don't think most people realize that more Americans die of lung cancer than die of breast, prostate, and colon cancer together. So it's a very major problem and one that needs more awareness so that we can support research and make more progress.

However, that being said, we have made a lot of progress in the last couple years which we'll talk about.

BANKHEAD: A lot of interest has been shown in the emerging role of mutations, mutation testing, and targeting therapies toward mutations. What are your thoughts about mutation testing at this point? Does it have a routine role, and what are some of the more common mutations that have been identified in association with non-small cell lung cancer?

SEQUIST: There's been a real sea change in the paradigm for diagnosing lung cancer in the last 5 years I would say. Whereas non-small cell lung cancer used to be considered one homogeneous group of patients, now it's become more and more apparent that there are several distinct subgroups of patients, and that they may respond very differently to available treatments, especially the newer targeted therapies. So it's becoming increasingly relevant to test for the mutations which define these subgroups because you can try to match the mutations to the treatments and get better results for the patients.

So the first lung cancer mutation to be discovered and the first one to have a matching, successful drug was the EGFR mutation, or epidermal growth factor receptor. Last year we saw FDA approval of crizotinib, a drug that matches with a second genetic biomarker in lung cancer, ALK translocations. At this year's ASCO meeting we heard about ROS1 translocations and how they also respond very well to crizotinib.

And there are many, many other examples of distinct subsets of lung cancer patients who respond to distinct targeted treatments. So genotyping is becoming a part of the everyday clinical world, it's not just a research modality anymore.

BANKHEAD: How widely available is mutation testing at this point?

SEQUIST: It's becoming more and more available. When the EGFR mutations were discovered in 2004 there were only a couple places that could clinically genotype patient samples. Now, in my speaking with different lung cancer docs all over the country, it seems like it's available for everyone. If your hospital or clinic doesn't do it in-house, there are a lot of send-out labs that will do EGFR mutation testing.

The ALK translocation, that's also becoming much more widely available now that there's an FDA-approved test that labs can purchase.

Some of the other newer mutation testing (for example, ROSI translocations) are not yet available everywhere, but I think that they will be once there are readily available and effective treatments that correspond to the genotypes. The future paradigm will be that as a mutation is discovered and a suitable drug match is found, that's really the impetus to send that testing out and make it available for all lung cancer patients.

BANKHEAD: If a test is available now would you encourage oncologists to send specimens if it applies to a particular patient?

SEQUIST: Yes. And broad genotyping does apply to most non-small-cell lung cancer patients, even today. The majority of the success stories reported so far have been in adenocarcinoma, but even at this year's ASCO, and this year's AACR, [American Association for Cancer Research] we're hearing about successful stories of genotypes and drugs for squamous cell cancer, such as FGFR1 (fibroblast growth factor receptor) amplification.

And the complicated part about trying to figure out if a patient sitting in front of you meets certain criteria for genotype testing is that each one of these genes may have a different clinical profile. This profile can be helpful in trying to figure out an efficient way of screening for one gene, but as soon as another clinically-useful genotype is described in a different clinical population you have a challenge trying to figure out which test to send for each patient. If you can imagine 3,4 or 5 clinically-useful genotypes as I think we will have very soon in lung cancer, pretty soon it gets so complicated that the easiest thing to do is to test each patient for everything targetable. It's kind of like if you think about a complete blood count, you may be worried about anemia, but you don't just check their red blood cell count, you get a complete blood count because that's the most efficient thing to do and it gives you a complete picture of what's going on in their bone marrow.

And I think that's how it's going to become with tumor genotyping too. Instead of trying to figure out which individual gene to test. I think we'll be screening for a broad panel of gene mutations on all the patients pretty soon.

BANKHEAD: You mentioned the issue of being able to match certain drugs with certain types of mutations. There are any number of EGFR inhibitors that have been developed. Which ones have specifically been tried in non-small cell lung cancer and have shown some benefit?

SEQUIST: There have now been six randomized trials that have compared, first-line EGFR-specific treatment to chemotherapy in EGFR mutants. Some of these trials have been with gefitinib (Iressa), the first EGFR-specific drug, and some have been with erlotinib (Tarceva). And then most recently we have seen the data about afatinib, which is a second generation EGFR TKI and pan-HER inhibitor that delivered improved PFS compared to cisplatin and pemetrexed chemotherapy.

So we've now seen phase III randomized trials using three different EGFR TKIs compared to several different combination chemotherapy regimens across multiple ethnic populations around the world. The results are strikingly similar across the board, namely that the personalized treatment with the EGFR TKI leads to a prolonged progression-free survival. And many of these studies, including the afatinib study, looked carefully at quality of life too, and they showed patients had a better quality of life when they went with the personalized treatment.

BANKHEAD: What is the status of conventional chemotherapy now and the management of non-small cell? I know there's a lot of excitement about the targeted agents, but the drugs that have been around for a while still are applicable, are they not?

SEQUIST: They are, and there have been some tweaks and updates in those drugs too, for patients without identifiable mutations. And even patients with identifiable mutations do need chemotherapy at some point as well. So we're now no longer thinking about chemotherapy as a one-size-fits-all thing, and the big distinguishing factor in determining chemotherapy is actually histology. So patients with a squamous cell non-small cell lung cancer are going down a different treatment algorithm that includes taxanes and gemcitabine as drugs, along with platinum, and patients who have non-squamous, predominantly adenocarcinoma, are going down a different pathway.

One of the most active drugs for those patients is pemetrexed. They can also get bevacizumab, whereas it's not safe for squamous cell patients. As well as the taxanes, gemcitabine and vinorelbine.

I would say the other big change in non-small cell lung cancer chemotherapy is this idea of maintenance that has emerged over the last couple years in a series of clinical trials showing that, if instead of what we used to give, which was four to six cycles of chemotherapy combination and then a break until patients had progressed, now we're seeing that there can be a survival benefit to continuing chemotherapy, either with the same drug or sometimes switching to a different drug, sometimes switching to a targeted agent like erlotinib.

But maintenance has really become part of the algorithm for treating lung cancer.

BANKHEAD: You mentioned some of the investigational agents that have been reported at AACR, ASCO, and other meetings this year. You mentioned afatinib as one. Were there some others in particular that have shown promise that caught your attention?

SEQUIST: Sure. I think at this year's ASCO there were a number of exciting things in lung cancer. There was a presentation about an immune modulating drug, and anti-PD1 antibody, that was very interesting. Immune therapy has been an appealing idea for a long time, that if you could get your body to attack the cancer and get rid of it itself that would be a great thing.

And there's been a lot of different research in different tumor types that has not panned out, with the notable exception of melanoma. But I think this year we saw the first real glimmer of hope about immune therapy in lung cancer with a drug that hits this anti-PD1, and they showed that there were some very impressive responses in all types of patients -- patients with adenocarcinoma, patients with squamous cell carcinoma, they had patients with different genotypes. So it's not clear if there is a biomarker, or which biomarker shows the patients that will do best with it, but I think there'll be a lot of exciting studies over the next couple of years looking at this compound and many others that other companies have in the works.

BANKHEAD: You mentioned the concept of going down different pathways. This was explored in a study known as BATTLE, moving toward what is being called "personalized medicine." Could you tell us a little bit about the personalized medicine approach and then your thoughts about how it may apply in the treatment of non-small cell lung cancer?

SEQUIST: I think that, as a field, lung cancer researchers have really seen a number of success stories in recent times by matching the tumor genotype to a specific treatment. The ALK story is one of the best examples, where a drug that was in phase I development, a first-in-man study, designed to examine safety, ultimately ended up leading to FDA approval because they really homed in on the group of patients that the drug worked best for - those with ALK translocations. After this experience, more and more drug development strategies are following this model. The BATTLE study at M.D. Anderson demonstrated the feasibility of re-biopsying patients to look at their genotype in the second-line setting. They studied patients who had previously been treated with chemotherapy and they obtained a biopsy on all patients before randomizing them to one of several different second-line therapies. They used genetic information from the biopsies to explore new biomarkers for the included treatments.

I think that concept of re-biopsying patients is really catching on now. At MGH, we have shown that rebiopsies on patients with EGFR mutations who have acquired resistance to tarceva can help steer them towards appropriate next treatments. Many new clinical trials are incorporation repeat biopsies too.

BANKHEAD: At some of the meetings I've attended this year, there have been discussions about how practical the re-biopsy approach is on a routine basis. What are your thoughts about what role it eventually might play?

SEQUIST: I think repeat biopsies for genotyping will become central to lung cancer care, but currently it depends on what options a biopsy may open up for the patient. If it's not going to change management at all, if you have no trials available or no targeted therapies that would be more or less appealing depending on what's found on a biopsy, then it may not make sense.

There are more and more therapies emerging that look like they will work better in certain patients than in others, making bio-marker evaluation clinically important. In addition, there are clinical trials in many different locations and biopsies may open up doors for patients to participate. For example, there's a large effort in the United States called the Lung Cancer Mutation Consortium, LCMC. This is a collaboration between over a dozen cancer centers around the country with a mission to test patients for a variety of lung cancer mutations and then match them with the most appropriate clinical trials.

So almost no matter what region of the country you live in, there's probably an LCMC site close to you where they would have trials that are open for certain genotypes. So if you had a biopsy and you found that your cancer had a KRAS mutation, for example, which is one of the most common mutations, they probably have at least one if not more trials available for KRAS lung cancer patients.

BANKHEAD: A lot of attention was focused on a large randomized trial suggesting that chest computed tomography is superior to standard radiographs for early diagnosis of non-small cell lung cancer. Where do things stand with that now? Is chest CT becoming the standard? I know there has been some talk about trying to find some sort of intermediate test that can identify patients who should go to CT. Where do we stand with that right now?

SEQUIST: I think this is a really important issue, because one of the problems with lung cancer is that the majority of patients who are diagnosed are diagnosed with late stage when it's no longer curable. Early stage lung cancer is more curable, and so if we can do more to find patients at an earlier stage it will really help.

It's been very challenging to diagnose lung cancer early because there aren't a lot of symptoms that are specific to lung cancer, and until last year there wasn't evidence that any kind of screening test was beneficial. But now that we know that screening high-risk patients with a low-dose CT scan can improve survival, both all-cause survival and lung cancer-specific survival, I think it's really changed the way people are thinking about it. And I know that a number of hospitals around the country have opened up screening programs.

There's still a lot of these details to be worked out, as you mention, as far as how often people should be screened, for how long, who exactly are the people who should be screened. And we have to set up systems to follow up on all the findings, make sure that nothing is missed on the scans that are performed. I think right now each hospital or each system is kind of going through those developmental processes, and there are lots of people doing research about things like cost effectiveness, and modeling different other types of imaging, and can we make this easier, can we make it cheaper or faster. But I think the bottom line right now is that screening does work for lung cancer, we have to start doing it, and we'll tweak it as we go along to do it in the best possible way.

BANKHEAD: As your interview has suggested, there has been a lot of activity in non-small cell lung cancer, a lot of areas where progress is occurring at the same time. How do you summarize this to your patients? What do you tell them in terms of what their future might be and what options they might have?

SEQUIST: Well, I do try and convey to all my patients -- because it is true and I really am passionate about it -- that advances are happening very fast in lung cancer research, and breakthroughs are coming every couple of months. And so for any patient sitting in front of me, I'm going to try and give them the best state-of-the-art treatments that are available at that time, but reassure them that even after they're done with one regimen, the state-of-the-art may be different and we'll keep pushing the envelope.

That being said, lung cancer is still a very deadly disease and we need more research and more research funding to start to change the game. Hopefully we'll have even more advances to discuss next year when we meet again.

BANKHEAD: Thank you very much.

For MedPage Today this is Charles Bankhead. My guest has been Dr. Lecia Sequist of the Massachusetts General Hospital in Boston. That's the end of this episode of Expert Commentary, Non-Small Cell Lung Cancer.

MedPageToday is a trusted and reliable source for clinical and policy coverage that directly affects the lives and practices of health care professionals.

Physicians and other healthcare professionals may also receive Continuing Medical Education (CME) and Continuing Education (CE) credits at no cost for participating in MedPage Today-hosted educational activities.